Obtaining high resolution images of joints, particularly the differentiation between bone and cartilage, can be of benefit for the diagnosis and treatment of disorders and diseases that affect joints and other regions of the body that are prone to inflammation of cartilage and other connective tissue. However, high resolution images of the boundary region between bone and cartilage can be difficult to obtain using standard imaging techniques. In addition, many imaging processes used in magnetic resonance imaging (MRI), such as in functional magnetic resonance imaging, require injections of various contrast agents in the patient either during or shortly prior to the data acquisition procedure. These injections often can cause immunologic or painful reactions and cause transient or lasting discomfort to patients.
MRI is a well-known medical imaging technique in which areas of the body are visualized via the nuclei of selected atoms, especially hydrogen nuclei. The MRI signal depends upon the environment surrounding the visualized nuclei and their longitudinal and transverse relaxation times, T1 and T2. Thus, in the case when the visualized nucleus is a proton, the MRI signal intensity will depend upon factors such as proton density and the chemical environment of the protons. Contrast agents are often used in MRI in order to improve the imaging contrast. They work by effecting the T1, T2 and/or T2* relaxation time and thereby influence the contrast in the images.
Several types of contrast agents have been used in MRI. Blood pool MRI contrast agents, for instance superparamagnetic iron oxide particles, are retained within the vasculature for a prolonged time. They have proven to be extremely useful to enhance contrast in the liver but also to detect capillary permeability abnormalities, e.g. “leaky” capillary walls in tumors, which are a result of tumor angiogenesis.
Water-soluble paramagnetic chelates, i.e. complexes of a chelator and a paramagnetic metal ion, for instance gadolinium chelates like Omniscan™ (GE Healthcare), are widely used MR contrast agents. Because of their low molecular weight they rapidly distribute into the extracellular space when administered into the vasculature. The problem with the in vivo use of paramagnetic metal ions in a MRI contrast agent is their toxicity and therefore they are provided as complexes with chelators which are more stable and less toxic.
In addition, there is presently a need for improved and reliable methods, particularly those that are non-invasive, for detecting early stages of osteoarthritis (OA), a debilitating disease that may be triggered by injury and reflects a complex interplay of biochemical, biomedical, metabolic and genetic factors. Chan, D. D. et al., “Probing articular cartilage damage and disease by quantitative magnetic resonance imaging,” Journal of Royal Society Interface 10, p. 1 (Jun. 8, 2012). The progression of OA is characterized by structural and mechanical changes in cartilage that progress from the superficial zone to the middle and then to the deep zones. Id. at p. 2. While radiography is the most common non-invasive imaging means to visualize the bone, it is not sensitive enough to detect earlier soft tissue changes. Id. Standard MRI techniques may be employed to assess changes in cartilage, including the thickness, surface area and volume. However, these measurements are nominal and may mask depth-dependent changes in cartilage, and are limited by the spatial resolution of imaging, the segmentation of regions of interest and the registration of images. Id. In addition, while standard MRI can be used to assess macroscopic changes to cartilage, it is not as sensitive to the biochemical changes associated with early stages of OA. Surowiec, R. K. et al., “Quantitative MRI in the evaluation of articular cartilage health: reproducibility and variability with a focus on T2 mapping,” Knee Surg. Sports Traumatol. Arthrosc., p. 1 (Oct. 30, 2013).
Compositional imaging depends on the composition of the cartilage tissue and new techniques are being developed for segmenting cartilage and delineating margins to enhance images to show changes in the cartilage matrix. Stanton, T., “New techniques improve cartilage imaging; dGEMRIC leads pack of new biochemical methods,” AAOS Now, April 2011 (http://www.aaos.org/news/aaosnow/apr11/clinical7.asp).
There is a longstanding, unmet clinical need for new and improved imaging agents, which provide high resolution imaging, decreased discomfort to the patient and increased tissue specific accumulation in the cartilage. In particular, agents that temporarily bind to the glycosaminoglycan and/or proteoglycan (e.g. chondroitin sulfate and keratin sulfate) and mucopolysaccharide constituents of cartilage (e.g. hyaluronic acid), such as those disclosed within this application, would enable the tracking of cartilage health currently inaccessible with non-invasive imaging.